Type 2 diabetes (T2D) is a devastating disease that has undergone a striking increase in prevalence in the U.S. and worldwide. Although a number of different drugs exist to help manage this condition, unfortunately more than 1/3 of affected individuals fail to achieve healthy blood glucose levels. Of the therapies used, metformin (i.e. Glucophage, a member of the biguanide drug class) is the most prominent of the drugs as measured by the number of prescriptions issued worldwide. Unfortunately however, up to 10% of potential patients cannot tolerate this agent because of gastrointestinal adverse effects while another, even larger, segment of the diabetic population with renal insufficiency cannot take metformin because of the risk of lactic acidosis, a life-threatening condition caused by a decrease in metformin elimination by the kidney. In the current revised application, a research plan is proposed to identify novel biguanides that can treat the segment of T2D subjects who are unable to take metformin or respond poorly to this drug. The plan is based on the transport of biguanides into liver and kidney cells by OCT1 and OCT2, respectively. In this approach, new biguanides will be synthesized by NovaTarg chemistry to increase their affinity for OCT1 while reducing their affinity for OCT2. We anticipate an increase in efficacy from the increase in uptake by the liver (OCT1), the target tissue of biguanides. Whereas a decrease in metformin elimination via the kidney (OCT2) is expected to make drug exposure predictable even in patients with impaired renal function. Thus, by changing the elimination pattern, the new biguanides will have the potential to be used by T2D subjects with renal insufficiency. The recent discovery that a third OCT, OCT3, acts to transport metformin into skeletal muscle has enlarged the scope of this work. In this revised application the novel biguanides will be tested for their activity on OCT3 and their ability to activate muscle AMPK. Although liver remains our primary focus on efficacy, compounds that can act on both liver and muscle should augment the control of blood glucose in T2D patients. As pointed out in our preliminary data, a chemistry plan is in place that has shown its ability to generate biguanides with improved selectivity for OCT1 over OCT2 when compared to metformin. Importantly in preliminary results, certain of these new biguanides have demonstrated an ability to activate AMPK in liver and muscle cells, to reduce hepatic cell glucose output, and to accelerate glucose disposal in mice as measure by an OGTT (see data for NT1014). These encouraging results argue for a successful outcome (i.e. a markedly improved metformin, both in efficacy and safety) in a drug class that has not experienced any significant innovation in over 40 years.